An AIDS vaccine approach combining adenovirus (Ad)-HIV recombinant priming with envelope protein boosting has been pursued. Chimpanzee studies demonstrated long-lasting protection against low- and high-dose HIV challenges without intervening immunizations. Only a minimal number of immunizations were necessary to elicit protective immunity along with antibodies capable of neutralizing primary and lab-adapted isolates. A role for cytotoxic T-lymphocytes in protection against low-dose challenge was also suggested. After boosting and a third re-challenge of the 3 protected chimpanzees with a non-syncytial- inducing primary isolate, one animal was completely protected and a second exhibited a reduced viral burden compared to the naive control. This first demonstration of protection against a heterologous primary isolate is highly encouraging and strongly supports further development of this vaccine approach. Priming of rhesus macaques with an Ad host range mutant-SIV recombinant and boosting with SIV envelope protein elicited humoral, cellular and mucosal immune responses. Upon intravaginal SIV challenge, the viral burden was reduced 10 to 100-fold during the acute infection period compared to control macaques. Notably, protection in both these systems was achieved using vaccines based only on the viral envelope. Addition of other viral components should significantly increase protective immunity. Further prime-boost studies in macaques using molecularly attenuated vaccinia SIV recombinants, with or without recombinant- expressed cytokine adjuvants, have shown induction of soluble CD8+ T-cell viral suppressive activity. Pre-challenge levels of this activity were correlated with steady-state plasma viral RNA levels post-intravenous SIV challenge. Moreover, high post-challenge levels correlated with non- progressor status while low levels correlated with rapid disease progression. These findings suggest future vaccine design should include induction of this suppressive activity. AIDS title: Adenovirus and Attenuated Poxvirus Vectors in AIDS Vaccine Development